Thursday, 31 January 2019

The paper by Vianna and colleagues [1] provides the blogging fodder today, discussing a potentially important topic around whether "the fetal brain infection caused by ZIKV [Zika virus] could predispose to ASD [autism spectrum disorder]."

Just before anyone gets the impression that a *link* has been found between Zika virus exposure and autism or autism spectrum disorder (ASD), I'm going to say no, not yet. The current peer-reviewed evidence at the time of writing this post has not identified autism as an outcome following exposure to the Zika virus. That's not to say that various other neurodevelopmental issues have not been associated with Zika virus exposure (see here for example) or that Zika virus exposure might not have biological consequences akin to that noted in some autism [2]. But as far as I'm aware, there is no peer-reviewed science yet suggesting that autism is for example, over-represented among those exposed to Zika virus in-utero. Not yet anyway.

Nonetheless, Vianna et al go through a number of lines of evidence suggesting how autism *could* be an outcome of Zika virus exposure. They start by talking about how Zika virus exposure during pregnancy can have a devastating effect on the developing child (see here) as a function of its teratogenic status. Severe microcephaly (small head size), a cardinal feature linked to infants' Zika virus exposure during pregnancy, has notable effects on the brain and its development, and is one of the more noticeable effects associated with Zika virus exposure in-utero. But further: "this phenotype is now considered only “the tip of the iceberg” and there is a spectrum of less severe abnormalities after congenital Zika infection."

Authors go on to talk about how pregnancy is a time of 'change' when it comes to maternal immune system functions, as a reprogrammed immune system has to become 'tolerant' of the developing foetus. Such reprogramming means that the foetus can survive and thrive. It also however means that the maternal immune system might be more susceptible to certain infections, where for example "opportunistic infections... take advantage." This is also the point where autism enters into the conversation, and the idea that exposure to various infections (viral and bacterial) occurring during pregnancy "can alter [offspring] brain development and are associated with alterations, such as brain calcifications, microcephaly, and neurodevelopmental disorders." I've covered a few possible examples on this blog with autism in mind (see here and see here).

Putting all this together, as well as talking about some of the immune system chemistry that *might* link Zika virus exposure and autism, and the authors come up with a model of 'neuroimmunomodulation' talking about "an ineffective anti-viral response" and increased levels of pro-inflammatory cytokines as being potentially important. I'll also provide another quote from Vianna which is similarly intriguing: "Moreover, in the case of ZIKV, previous infections with other flaviviruses, such as dengue virus and yellow fever, may trigger a secondary immune response of differential magnitude given the great molecular similarity of some immunogenic epitopes among these correlated viruses."

Reiterating that there is currently no link between Zika infection and risk of autism, I do find the Vianna paper interesting. It offers some testable hypotheses that could examined in the lab and beyond. It also provides some further support for the various surveillance and monitoring initiatives that remain in place with regards to Zika virus and the promise of further important data to come from them.

That was the quite sweeping statement made in the paper published by Beata Jarmołowska and colleagues [1]. It continues a quite a long running research topic in autism circles (see here and see here) on whether the chemical arrangement of certain dietary components *might* have an important biological effect on at least some people diagnosed as being on the autism spectrum.

The Jarmołowska paper is open-access so there is no real need for me to go over the suggested hows-and-whys of some diets being potentially related to (some) autism. If you need some further reading on the topic, I'll direct you to other posts on this blog where I've discussed this 'gluten and casein' issue (see here) and onward, my professional interest in it for quite a few years.

The aim of the Jarmołowska study was to determine "BCM7 [β-casomorphin-7] influence on DPPIV functioning in children with ASD in comparison to healthy children." 'Healthy children' is the term for the control group used by the authors by the way, not me. They "examined content and activity of serum DPPIV, content of BCM7 in serum and urine, and studied the effect of hydrolysed bovine milk, as a source of opioid peptides, on DPPIV gene expression in peripheral blood mononuclear cells (PBMC) in both groups."

Results: "We found that the content of BCM7 in serum was significantly higher (p < 0.0001) in ASD than in the control group." Urine concentrations of BCM7 were not significantly different among those with autism compared with controls. Also: "Concentration of DPPIV was found to also be significantly higher in serum from ASD children compared to the control group (p < 0.01)."That was about the sum of the differences noted by researchers.

Caveats? Well some. So: "ELISA test enabled identification of BCM7 contents in the serum and urine from patients, as well as in tested peptide extract obtained from hydrolyzed bovine milk." Authors do mention how the testing was carried out "in triplicate" following a previously published protocol. I don't dispute the results they got but am not exactly enamoured with the ELISA method used. I'd much rather see the analysis undertaken using something like mass spectrometry or similar technology, given the precision that comes with such methods (see here) based for example, on the use of internal standards. Perhaps if the authors still have their samples, they might consider further analyses if available to them?

Although researchers provide quite a bit of information about their participant groups, I also noted one important detail to be missing: were any of their participants - diagnosed with autism or not - following any special dietary regime? Y'know, they talk about casein (milk) free diets and how such diets are supported by "numerous scientific reports." So I guess in a cohort of 86 children diagnosed with autism, at least a few of them might be following such a dietary intervention? I've searched their paper but couldn't find anything to say that they were or weren't.

Putting such issues to one side, I don't want to take anything away from the Jarmołowska findings. As they end their paper: "this issue requires further investigation." I wouldn't disagree.

I appreciate that such a study is probably not going to be everyone's cup of tea given, for example, the rather *interesting* history of colostrum and autism (including the words 'transfer factor' [2]). The Sanctuary study however, should be taken on its own merit regarding "concurrent supplementation with both the probiotic B. infantis and bovine colostrum product (BCP) as a source of immune factors and prebiotic glycans could alter the microbiota to a more beneficial composition in order to improve gut health in children with ASD and GI symptoms." The rationale behind such work is that (a) what goes on the in the deepest, darkest recesses of the GI tract in a microbial sense could impact on the functional gut symptoms, and (b) said functional gut symptoms seem to be 'over-represented' in relation to autism (see here) and *could* in some cases, be linked to behavioural presentation (see here). Ergo, try and impact on functional gut symptoms and one *might* be able to impact on behaviour...

Sanctuary et al report preliminary findings designed to "assess tolerability" and "to evaluate GI, microbiome and immune factors in children with ASD and GI co-morbidities." This work represented a first step towards a bigger research trial to ascertain whether such a supplemental combination *might* be useful for some people on the autism spectrum in a 'clinically relevant' sense. Despite being a pilot study, researchers did conduct what is considered a gold-standard study insofar as it being a "double-blind, crossover, randomized clinical trial (RCT)." The study protocol was also research registered (see here), so quite a few methodological boxes were ticked.

Given that this study was carried out at the MIND Institute, an institution that has quite a lot of experience in all-manner of different autism research areas (see here and see here), researchers were pretty precise when it came to diagnosing autism/ASD and ascertaining the presence or not of GI symptoms in their small cohort (N=11). The authors also provide quite a bit of information about the supplements used including "the bovine colostrum product (Imucon)" and details of its safety: "The product was tested and found to be negative for Escherichia coli, Salmonella, Listeria, coagulase positive Staphylococcus and antibiotic residue." Insofar as dosages, we are told that: "The colostrum powder dose administered in this study was 0.15 g/lb body weight per day" and "The probiotic dose administered in this study was 20 billion CFU [colony forming units] per day." A couple of supplemental combinations were examined during the study including BCP on its own and BCP+probiotic.

Results: there were quite a few different types of results reported on for 8 of the original 11 participants. Importantly: "Bovine colostrum product appears to be well-tolerated in these children [diagnosed with autism] as its own treatment as well as when combined with the probiotic B. infantis." 'Well-tolerated' means that there were "no participants needing to withdraw due to adverse events" despite a small number of reports of things like gassiness. A couple of kids were also reported to find the taste of the products not too great.

Also: "Some participants on both treatments saw a reduction in the frequency of certain GI symptoms, as well as reduced occurrence of particular aberrant behaviors." Being really careful here because of the small participant number included for study for example, researchers reported that "87.5% (7/8) of participants exhibited some improvement in GI symptoms while on the BCP only arm and 100% (8/8) of participants exhibited some improvement in GI symptoms while on the combination treatment arm." The sorts of GI effects mentioned included reductions in "pain with stooling, frequency of diarrhea, and consistency." Researchers also reported that appetite seemed to be improved for some kids too, particularly the consumption of fruit and meat.

A few other changes were noted in the study, but on the basis of the small participant size and the aims of the study I'm gonna leave them for now. As the authors mention: "the lack of a clear control group receiving a placebo" means that this was a "cross-over study where each participant was his own control" and therefore one needs to be cautious for now. What is needed next is a larger trial and more focus on the behavioural presentation side of autism...

The reasoning behind my reticence was primarily to do with the study design whereby "a 4-day group intervention program, comprised by education, cognitive group therapy sessions, mindfulness sessions, physical activity and writing sessions, within a context of cognitive behavioral therapy, mindfulness, acceptance and commitment model" was delivered to over 300 people diagnosed with Chronic Fatigue Syndrome/Myalgic Encephalopathy (CFS/ME) and self-report results plotted "1 week before and 1 week after the intervention program, and at 3 months and 1 year after the intervention" without any control group or any kind of blinding. Even the researchers themselves wrote that their study design make "conclusion of the actual effect of the treatment program [in part or whole] and its impact on the clinical course through the follow-up period difficult." But, here I am...

As you can see from the picture accompanying this post, others are also just a little bit critical of the Stubhaug paper and findings. Although I can't speak for anyone else, I imagine some of the 'criticism' of the study and results rightly follows on from the methodology employed by the authors. I did also wonder if some feeling might also be there because of the subject matter, and specifically, the continuing idea in some quarters that the application of the biopsychosocial (BPS) model to CFS/ME should carry weight. To quote from the authors: "The therapeutic rationale behind the program was to increase the medical knowledge and interpretation of bodily distress, challenge and modify dysfunctional illness perceptions as well as illness behavior, and through acceptance and commitment strategies contribute to behavioral change and clinical improvement." Sounds about as BPS as you can get I reckon.

Focusing for now on the methodological and related side of the Stubhaug paper, the starting point for the study was the authors' observation that: "The most promising treatment so far seem to be cognitive-behavioral treatment programs... and graded exercise." Just before anyone gets angry about this, authors do also highlight how "the effectiveness of interventions and robustness of findings are continuously being questioned" in this area. Yes, yes they are being questioned (see here and see here for examples) and by lots and lots of different people. Nonetheless, researchers decided to test whether their 4-day program, encompassing quite a few elements, might impact on some of the signs and symptoms of CFS/ME in their cohort. Said program included education: an "introduction to stress medicine with focus on physiological and psychological stress", cognitive group therapy, mindfulness and writing experience ("patients were instructed to write for 15 min about positive experiences and emotions"). They also talk about the use of "daily walking sessions of 60–90 min, in low to moderate pace" which, considering other research (see here), sounds pretty 'full on' to me, in light of some of principal issues that define CFS/ME (see here).

Relying on self-report measures such as the Chalder Fatigue Scale and the Short Form Health Survey-36 (SF-36), researchers reported their results as per the timescales already mentioned. The picture that emerged was a fairly positive one as various statistically significant group changes (improvements) were noted across the testing sessions, even when taking into account different ways of diagnosing CFS and across the various instruments used. Most participants also said that they were pretty satisfied with the intervention program and the service they received. In short, the study met it's aims quite successfully.

But... not to pour cold water on the findings, one cannot forget about the 'open study' shortcomings of the study design. So on top of what has already been mentioned: "Many patients with CFS/ME tend to be critical to biopsychosocial interventions, and possibly most of these patients did not accept referral to the clinic, contributing to the possible selection bias." I'd say that this was another quite important *issue* that faced the Stubhaug study. The authors go on to note that their results "clearly represent a CFS population, albeit not representing the total body of CFS/ME patients" so perhaps clarifying the caution needed in this area of science specifically around any sweeping generalisations. And as an example: "At 1 year follow-up, half of the patients completing assessments (56%) still report levels of fatigue representing substantial fatigue." Such an intervention is therefore no panacea for CFS/ME.

What else? Well, the continued focus on subjective questionnaires over and above more objective measures is also apparent in the Stubhaug findings (see here). As I've mentioned on more than one occasion, it's perfectly acceptable to ask patients how they are feeling and about related issues like quality of life for example (see here). But when it comes to a condition or set of conditions like ME/CFS defined by fatigue and other symptoms that very much impact on core issues such as activity, it strikes me that one should really include an objective measure of activity if one wants to study it in its entirety. So yes, actigraphy would have been a good feature to see in this study (with before and after results). Even a pedometer costing a few quid, used a few times a week over a number of different weeks would be something at least. And once again, how about also including some biological parameters into such studies too? Y'know, just on the off-chance that things like mindfulness, minus any grand sweeping claims, for example, could have possible biological effects too [2]?

Saturday, 26 January 2019

"These results highlight the importance of early surveillance of children who are at elevated risk for ASD [autism spectrum disorder], and early initiatives should focus on early signs of the phenotype, including both movement and sensory differences (prodromal signs) prior to the emergence of diagnostic characteristics."

Although open-access, a few details might be useful: "Infants were selected at random to comprise three groups of equal size: (1) 10 non-sibling controls (LR [low risk]-control; 7 boys); (2) 10 HR [high-risk] siblings without an ASD diagnosis (i.e., with an older sibling with ASD but did not receive an ASD diagnosis themselves at 36 months; HR-N; 3 boys); and (3) 10 HR siblings with an ASD diagnosis (i.e., with an older sibling with ASD and also received an ASD diagnosis at 36 months; HR-ASD; 6 boys)." As you can see the participant numbers were fairly small but to balance this, authors did report results based on testing "for differences in reaching-to-grasp" across quite a long period (6-36 months) and utilised quite an array of psychometric testing tools pertinent to their population and study aims.

Researchers found that: "Children who were later diagnosed with ASD showed higher (worse) total scores on the reach-to-grasp movement, as well as higher scores on the components of Orient, Lift, and Pronate compared to children in the LR and HR-N groups." They concluded that: "results suggest that such movement mechanics are relevant to monitoring motor development in children at risk for or diagnosed with ASD." Ergo, there may be quite a bit to see when it comes to early surveillance for autism in respect of movement and/or sensory differences.

Just before you leave I'll also bring the findings reported by Emilia Biffi and colleagues [2] to your attention. Theirs wasn't so much a study of the possible early 'prodromal' signs of autism with a focus on movement patterns but rather another finding suggesting that such movement issues may be persistent in relation to autism and can be readily tested for. Utilising some pretty nifty movement capture technology - "an immersive virtual environment using a 3-D motion analysis system with a dual-belt, instrumented treadmill" - Biffi et al reported that their findings "depicted gait peculiarities in children with ASD, including both kinetic and kinematic features." Movement and gait issues it seems, may very well be a vitally important part of autism...

Mental health also figures in the Long Term Plan, as this area continues on its 'parity of esteem' journey (see here). Being careful not to label autism as a mental health condition, I note that autism and learning (intellectual) disability also gets a mention in the Plan for quite a few reasons...

So, starting on page 52 of the report: "Action will be taken to tackle the causes of morbidity and preventable deaths in people with a learning disability and for autistic people." It's about time that this was 'tackled'. I say that because the statistics on early mortality with autism in mind are truly, truly shocking (see here and see here). It's also of interest that the LeDeR (Learning Disabilities Mortality Review) initiative is mentioned in this context too (see here). How exactly such inequalities will be tackled is however, not precisely detailed in the Long Term Plan.

Then: "The whole NHS will improve its understanding of the needs of people with learning disabilities and autism, and work together to improve their health and wellbeing." Allied to improving uptake of annual health checks that should be available, the document talks about working with partners to "bring hearing, sight and dental checks to children and young people with a learning disability, autism or both in special residential schools." It's a start given what said overlooked issues might be involved with (see here) but what about this who aren't in special residential schools? The Plan also mentions how: "By 2023/24, a ‘digital flag’ in the patient record will ensure staff know a patient has a learning disability or autism." I believe this would also solve a few 'issues' with regards to the (estimated) prevalence of autism and/or learning disability here in Blighty (see here and see here).

Also: "Children and young people with suspected autism wait too long before being provided with a diagnostic assessment." Yes, yes they do (see here). The Plan therefore sets out to "test and implement the most effective ways to reduce waiting times for specialist services." You've got to be kinda careful with the wording here because, as far as I can see, there is no commitment to a timescale of diagnosis unlike the commitment to reducing those with autism being accommodated at inpatient units for example: "By March 2023/24, inpatient provision will have reduced to less than half of 2015 levels (on a like for like basis and taking into account population growth) and, for every one million adults, there will be no more than 30 people with a learning disability and/or autism cared for in an inpatient unit".

I'll leave readers to decide whether this Long Term Plan represents something 'good for autism' or just skirts around some of the bigger issues. Personally I see some positives and some 'missed opportunities'. Positives? Well as I said, anything that can impact on those shameful early mortality figures in the context of autism is a good thing. I do have questions about how issues like suicidality, that contribute quite a bit to the early mortality stats, are for example, going to be addressed, but if lives are going to be saved and hopefully enhanced, I'm all for that. Reducing waiting times for assessments is also a good thing, as is the idea of the 'digital flag' to (hopefully) help enhance the doctor-patient interaction where autism is a feature.

Negatives? Well, there doesn't seem to be a great amount of details mentioned and even less discussed about adult autism and what the Long Term Plan is going to do for the thousands of autistic adults (many of whom are not also described as 'learning disabled'). There are many pressing issues for this group (see here and see here), some of which cross-over with the primary tenets of the Long Term Plan (see here) with autism in mind. It strikes me that there is much more to do in this area.

I specifically wanted to talk about this paper because of the word 'payback' and it's particular use to mean an "increase in fatigue and symptoms following activity." Mentioning it only twice in their article (one of those occasions being the use of a reference), I think the authors mean post-exertional malaise (PEM) (see here and see here for more discussion of this concept). They however, seemed a little reluctant to use that term. In answering one of the reviewers of their paper prior to acceptance for publication, the authors did say: "Payback is defined as a core symptom in NHS guidance, and is used in the clinical setting." They also clarified how "the term ‘payback’ was used instead of exhaustion."

No mind, based on interviews with "21 adolescents and their parents (20 mothers and 2 fathers)", most adolescents being female with a mean age of around 14 years, several key themes emerged. To reiterate: "All adolescents with CFS/ME report fatigue, a natural fluctuation of the condition, as well as an increase in fatigue and symptoms after activity (payback)." Several sub-themes also emerged from such reporting including how: "Adolescents and parents reflected on how CFS/ME naturally fluctuates" and "Adolescents and parents recognised patterns of good and bad days" and "Adolescents were limited in the amount of time they could spend on activities, which ranged from minutes, ‘5 min’ to hours, ‘an hour at the most’." These aren't exactly novel findings by any means but it's always useful to see them described in the peer-reviewed research domain.

Heading back to that 'payback' issue, researchers mention how their results are "consistent with previous research where children described the intensity of symptoms fluctuating as well as ‘overextension’ making it worse, resulting in ‘paying the price’." Accepting that such payback or PEM or 'payback exhaustion resulting in fatigue and other symptoms following activity' if you prefer, is widely present in CFS/ME (albeit individual and 'variable' in nature), one might see the Parslow results perhaps as further justification for being slightly critical of the use of something like graded exercise therapy (GET) in relation to CFS/ME (see here). GET relies on the assumption that increasing or grading in physical activity will eventually 'help' facets of CFS/ME. Unfortunately, whilst still expounded in some circles, there is accumulating (peer-reviewed) evidence that many patients with CFS/ME experience GET as more of a hindrance rather than a help for their symptoms (see here). Indeed, allied to terms like 'deconditioning' as part of suite of 'psychobabble' that seems to have enveloped CFS/ME down the years, the idea that CFS/ME is something that can be just 'exercised out of' seems to have been a truly damaging policy that has not seemingly served many patients particularly well.

The Parslow findings are revealing and add something further to the idea that an overhaul of current thinking on CFS/ME in children and adults is perhaps required (see here). Obviously the results are small-scale and require some follow-up, but listening to patients and their parents/caregivers and their collected experiences is a good idea in my book; particularly when it comes to a group of conditions like CFS/ME that have seen more than their fair share of 'assumptions' down the years.

The aim of the Cheung study was to "assess referral numbers and describe the sociodemographic and clinical characteristics"of their cohort, with specific reference to the prevalence of ADHD and/or ASD (autism). The autism 'connection' (and why I'm blogging about this research) follows quite a bit of other research suggesting that gender identity issues and/or reassignment behaviours *might* be over-represented when it comes to a diagnosis of autism (see here and see here and see here for examples). I stressed the word *might* because, so far, there is still some doubt about whether autism / autistic features is / are the more important variable above other comorbid features or comorbidity (see here). I'll also come to the idea of whether 4.8% is actually 'over-represented' or not when it comes to the autism [prevalence] numbers game shortly...

Based on data for quite a large number of individuals (N=540), researchers arrived at those pretty standout figures for various psychiatric and behavioural comorbidity being present. They use the words 'not surprisingly' when it came to the depression and/or anxiety prevalence stats garnered, and how "discrimination and difficulties accessing gender-affirming treatments" may be a contributory factor. I'd also draw your attention to the finding that: "Despite relatively high levels of education, unemployment rates of 21.3% were high in this relatively young cohort, four-fold higher than the Australian general population unemployment rate of 5–6%" as another possibility to (partly) account for some of those psychiatric features / diagnoses being reported on (see here).

So, 4.8% of the cohort with ASD. Is this a particularly high figure? Well, it depends. The authors rely on data from the Australian Bureau of Statistics (2015) which listed 0.7% as the "Australian population prevalence" of autism or ASD. I've not been able to find much more in the way of published estimates of adult autism specifically in Australia but would perhaps hazard a guess that 0.7% is likely to be an underestimate of the true autism rate on the basis of other population data for example (see here). Bear also in mind that Cheung et al also relied on "consecutive consultations between 1st January 2011 and 31st December 2016" so covered quite a long period of time period over which referral data was collected.

The Cheung study also ventures into some of the possible hows-and-whys of autism (and ADHD) being potentially over-represented among their transgender cohort. I'm not going to head too much into what these might be here because the long-and-short of it is that we don't know about possible overlapping genetics for example (although autism genes aren't necessarily just genes for autism) or even whether non-genetic factors might be at work: "it has been suggested that endocrine disruptors such as prenatal exposure to phthalates or antidepressants may be an explanation for the increase of ADHD and ASD and relationship with gender variance" (authors words not mine). Likewise whether the presence of autism or autistic traits means that someone is more or less likely to be 'socially conforming' is something that cannot be confirmed or denied in relation to gender variance at the present time.

All I will say is that more research is indicated in this area. Preferential screening for a range of developmental / behavioural / psychiatric issues is probably also implied as and when someone clinically presents for gender-related issues, in order to ensure that the care they receive is tailored specifically to them.

Informing policy is just what the Stiglic/Viner paper did (see here), as the Royal College of Paediatrics & Child Health (RCPCH) concluded that: "Many of the apparent connections between screen time and adverse effects may be mediated by lost opportunities for positive activities (socialising, exercise, sleep) that are displaced by screen time" but parents shouldn't necessarily get too stressed if their offspring find some enjoyment in their computer/tablet and/or phone in amongst their busy lives. Indeed it was refreshing to see that children and young peoples' voices were being heard on the potential benefits of screen time, with comments such as: "Gives you knowledge" and "Provides you with more opportunities to reach a wider community." All those hours of watching You Tubers fooling around or building whatever on Roblox or similar platforms can actually be intermixed with something approaching gaining knowledge; i.e. learning. Who knew!

The Stiglic/Viner review paper drew on data from 13 reviews reporting "associations between time on screens (screentime; any type) and any health/well-being outcome in CYP [children and young people]." All was not however completely rosy when the reviews were boiled down to a consensus, as we are told that authors found "moderately strong evidence for associations between screentime and greater obesity/adiposity and higher depressive symptoms" and "moderate evidence for an association between screentime and higher energy intake, less healthy diet quality and poorer quality of life." I don't think anyone should really be surprised that more screen time *might* mean an increased tendency towards being overweight or obese. If one subscribes to the idea that energy in - energy out is at least partially related to being overweight or being obese [2] it stands to reason that unless people are running around whilst using their tablets or phones, there is likely to be less 'energy out'.

As for the 'higher depressive symptoms', well let's just say that this is something else that is no stranger to the debate about screen time, as other recent research has similarly observed (see here). Whether it is the actual use of tablets, phones and/or television or the type of material being accessed [3] *correlating* with depression is a question that needs further investigation. I might add that the scenario of when screen time turns into an addiction also needs to be discussed in this context (see here), bearing in mind the limitations of observational studies in relation to discerning cause-and-effect.

Also: "There is weak evidence for association of screentime with behaviour problems, anxiety, hyperactivity and inattention, poorer self-esteem and poorer psychosocial health in young children." Bearing in mind that 'weak evidence' does not mean 'no evidence', this part of the Stiglic/Viner review paper is also important. It means that sweeping conclusions that screen time is somehow playing a major role in the rise of behaviour problems in children (young and old) are not yet necessarily backed up by the scientific evidence. Indeed, as per other topics on this blog, I'd advance the position that certain facets of screen time may actually be advantageous to quite a few children and young people (see here) who are perhaps not for example, the social butterflies that other children are.

The Stiglic/Viner review and subsequent RCPCH advice does not say that screen time for children is risk-free. It does not say that parents shouldn't be continually asking questions about how long their children spend using screens and/or what material they are accessing. It does however mean that, on the basis of the currently available evidence, parents shouldn't get too stressed about moderate screen use in their offspring. Balance things out with the odd physically active inclined hobby or two (avoiding any tiger parenting notions) by all means, but don't stress too much about their swiping. See the potential positives as well as the potential negatives of screen use, and remember that screen time is an inevitable part of growing up these days...

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[1] Stiglic N. & Viner RM. Effects of screentime on the health and well-being of children and adolescents: a systematic review of reviews. BMJ Open. 2019;9:e023191.

[2] Malhotra A. et al. It is time to bust the myth of physical inactivity and obesity: you cannot outrun a bad diet. Br J Sports Med 2015;49:967-968.

Monday, 21 January 2019

Hyperemesis gravidarum mentioned in the title of this post refers to "prolonged and severe nausea and vomiting" during pregnancy alongside other symptoms. It's thought to affect only a relatively small percentage of pregnant women despite vomiting and nausea being pretty common throughout many pregnancies. Indeed, hyperemesis gravidarum (HG) is much more than just nausea and vomiting.

The findings reported by Marlena Fejzo and colleagues [1] looked at the "neurodevelopmental outcomes of 267 children delivered by 177 mothers with HG were compared to neurodevelopmental outcomes from 93 children delivered by 60 unaffected mothers." The study was undertaken on the basis that previous published research from this study group [2] had identified "neurodevelopmental delay" as a possible *correlate* tied to HG exposure during pregnancy. That being said, on that last occasion researchers also described finding "no evidence for increased risk of 13 emotional, behavioral, and learning disorders, including autism, intellectual impairment, and obsessive-compulsive disorder" in their cohort.

This time around: "Similar to at age 8, the children (now 12) exposed in utero to HG had over 3-fold increase in odds of neurodevelopmental disorders including attention, anxiety, sensory, sleep difficulty, and social development delay/social anxiety." With a longer follow-up period, researchers also reversed their 'no evidence for increased risk' sentiments with regards to a diagnosis of autism in their cohort. So: "there was also a significant increase in Autism Spectrum Disorder (ASD), reported in 22/267 (8%) of children exposed to HG in utero and no unexposed children."

Let me be clear on this: these latest results on their own don't necessarily mean that HG *causes* offspring autism. Although 8% of the HG exposed group reporting autism or ASD seems quite high, it has to be seen in light of an increasing (estimated) prevalence of autism more generally (see here and see here). I'd also suggest that as with many other pregnancy/gestational factors put forward as potentially influencing offspring autism risk, one needs to be mindful of the issues involved in teasing out which is the important variable from potentially many (see here and see here).

But... further investigation is indicated in this area. Indeed, I hark back to the findings reported by Andrew Whitehouse and colleagues [3] who observed a "strong, positive association between increasing frequency and severity of NVP [nausea and vomiting during pregnancy] and ASD severity in offspring." No, not necessarily HG, but an implication that some of the overt features of HG might hold some *connection* to offspring autism risk for whatever reasons...

Under systematic review and meta-analysis conditions, researchers basically found what many people had suspected for quite a while, insofar as maternal weight, before or during pregnancy, being a 'risk factor' for an offspring diagnosis of autism or ASD. They arrived at their conclusion based on "13 eligible studies for meta-analysis (involving 943,293 children and 30,337 cases)" which collectively found that "both maternal obesity... and maternal overweight... were significantly associated with ASD, while maternal underweight was not associated with ASD." Researchers also looked at paternal weight as a possible risk factor for offspring autism but found no statistical association between paternal obesity, overweight or underweight based on the available data (limited to only three studies).

Mindful of the potential for 'stigma' to set in with such investigation, and likewise being careful not to generalise too much from such findings, the Lei results point to both the requirement for more research in this area and a possible 'intervention' route towards reducing the risk of offspring autism: "pre-pregnancy weight control is suggested." I've covered this topic numerous times on this blog (see here and see here and see here for examples) and have concluded that whilst correlation is not the same as causation and that pre- and peri-pregnancy weight is often intricately tied into other features of the condition known as metabolic syndrome, immune function and in particular inflammation, are perhaps important areas for further assessment. Research should perhaps head in that direction, and see what further crops up...

Friday, 18 January 2019

The brief letter by Michael White [1] talking about how: "Clinicians need to be mindful of the possibility of undiagnosed autism in all patients with TRD [treatment-resistant depression]" was a bit of an eye-opener. White who lists "has an adult son with autism" on the 'competing interests' section of his publication, offers an interesting perspective in relation to TRD (described as those "who do not respond adequately to a course of appropriate antidepressant medication within a certain time").

The letter from White is brief but covers quite a few important issues including (a) the observation that autism rarely exists in a diagnostic vacuum when it comes to psychiatric and/or behavioural labels (see here) and (b) the quandary of whether depression occurring alongside autism is a 'comorbidity' or something rather more 'core' to at least some autism (see here). That last point in particular is an important one given how many times depression has cropped up in the peer-reviewed research literature with autism in mind and onward whether certain typically indicated interventions for depression are actually cutting the clinical mustard where autism is mentioned (see here).

I am slightly cautious not to go 'all in' with the idea that every case of TRD is just undiagnosed autism. There are multiple other potentially important things to consider where depression - treatment resistant or not - presents (see here and see here for examples) over and above a diagnosis of autism or the presentation of clinically significant autistic features. But there could be some merit in physicians at least thinking about undiagnosed autism as and when TRD presents...

Some basics from the Barone study: "A targeted panel of 45 ASD analytes including acyl-carnitines and amino acids extracted from DBS was examined in 83 children with ASD... and 79 matched, neurotypical (NT) control children." Autism was confirmed as autism in the 83 autistic children, also including the application of some important exclusionary criteria such as a "positive history for mitochondrial disease or known medical conditions including autoimmune disease and inflammatory bowel diseases (IBD)/celiac disease." I was also happy to see that researchers screened for 'possible autism' in their control participants too: "The Social Communication Questionnaire was used to screen and exclude autism in TD [typically developing] children."

Although the Barone study was a study predominantly analysing dried blood spot samples (a sample medium that has always been slightly under-utilised in research circles), researchers did also look at urine and blood samples obtained during the course of their study. They reported some interesting observations as a consequence of analysis; notably that: "Twenty-five out of 40 studied [autistic] subjects (62.5%) had significantly decreased blood Vitamin D3 levels with normal Ca/P ratio." Decreased vitamin D levels are no stranger to autism (see here and see here).

Insofar as the 'ASD analytes' results, we are told that 8 acyl-carnitines were significantly increased in the autism group compared to the control (not autism) group. I'm not going to bore you with the specific details but suffice to say the list of compounds was pretty robust and "confirm the same, unique pattern of acyl-carnitine profile" as noted in other studies with other groups. Researchers also mention how one particular amino acid - citrulline - was also significantly increased in the autism group compared to controls. They talk about how: "Blood citrulline level is considered a biomarker of gastrointestinal mucosal surface and enterocyte integrity" among other things and could have some implications for that and other 'effects'.

And then something else: "The present study confirms that patients with ASD may show a distinct metabolic profile, demonstrating that this can be used to identify a subset of ASD patients with respect to TD at younger ages." I'm always a little bit wary of studies talking about biomarkers and autism (see here for another example) but the important use of the word 'subset' denoting how autism is a label covering significant heterogeneity makes me feel a little easier about such sentiments (see here and see here) albeit with much more study being required.

Wednesday, 16 January 2019

There was something rather intriguing about the results published by Liisa Salmela and colleagues [1] (open-access available here) observing that: "Elevated levels of autistic traits were significantly associated with shorter weekday sleep duration" in a cohort of adolescents from Helsinki in Finland. The fact that researchers also concluded that "autistic traits remained an independent predictor of short sleep duration when comorbid psychiatric symptoms were controlled for" added to the intrigue.

I was impressed with some elements of the Salmela study; notably the use of actigraphy as an objective measure of sleep accompanying self-report data derived from the Pittsburgh Sleep Quality Index (PSQI). The fact that actigraphs were worn "continuously for an average of 8.36 nights (SD = 1.76; range 4–17)" also meant that researchers had access to quite a bit of data from their 150+ participant study group when it came to activity cycles covering sleep.

What was the measure of autistic traits used I hear you ask? Well, we are told that: "Autistic traits were assessed using the Autism Spectrum Quotient (AQ)" which is an OK measure I suppose, although not without some shortcomings in terms of what is being specifically measured (see here). I should also mention that for the most part, the Salmela study was a study of non-autistic adolescents (two participants were reported to have "scored at or above the clinical cut-off score of 32" on the AQ).

"Continuous autistic traits significantly predicted weekday total sleep time" and "having elevated autistic traits as measured by AQ (Autism Spectrum Quotient) increased the risk for short sleep duration." Mindful that correlation is not necessarily the same as causation, details were important to the Salmela findings as we are also told that (a) as a group, boys tended to score higher on the AQ and (b) again as a group "boys had significantly shorter weekday total sleep time" than girls. It's perhaps no surprise therefore that: "Sex had a statistically significant main effect (p = 0.032) on total sleep time."

Next question: why? Why should autistic traits potentially "increase the risk for short sleep duration in a general adolescent population"? Is there something about the presentation of autistic traits that affects sleep either through psychological/cognitive processes or more physiological processes? Well, those are questions that still need answering. And alongside we seem to have yet another example where core autistic features may very well impact on so-called comorbid issues to add to the collection (see here and see here). This also has potential implications for intervention too...

Same as on the previous paper by Tseng and colleagues [2] I'll mention having a minor part to play in authoring the latest Tseng paper, and how such participation will in no way interfere with my hopefully critical musings on this latest publication.

The name of the research game this time around was to 'meta-analyse' the currently available collected peer-reviewed research literature into some sort of coherent 'where we're at' statement on the topic of breastfeeding practices and offspring ADHD risk. This wasn't about 'making' any new data; just synthesising what is already there on some specific topics: "(1) the difference in the duration of maternal breastfeeding between children with and without ADHD, and (2) the association between maternal breastfeeding and ADHD in children." A total of 11 articles pertinent to those research questions were identified and information was 'boiled down'.

Results: "an association was found between non-breastfeeding and ADHD children (adjusted OR = 3.71, 95% CI = 1.94 to 7.11, p < 0.001)." At first glance this looks like a pretty impressive *relationship* between 'non-breastfeeding' and the presence of a diagnosis of ADHD in offspring. It is, but it might not necessarily mean what you first think. Authors do mention how the early presentation of certain ADHD or possibly related traits might not have been conducive to successful breastfeeding behaviour to the point where a lack of 'cooperation' could have led to less breastfeeding. I'm not saying this is THE reason for the results we reported; merely that it is one possibility to entertain. There may also be other factors to take into consideration too (see here for example) minus any sweeping generalisations.

Whilst I am cautious about making too much of the Tseng findings - subsequent individual studies have reported no link [3] - other, more recent meta-analyses have arrived at similar conclusions to Tseng [4]. Yes, the Zeng paper [4] looked specifically at breastfeeding duration, and yes it was a meta-analysis that overlapped with material used in the Tseng study. But the conclusion - "maternal breastfeeding may reduce the risk of ADHD in children" - is similar, and again suggests closer inspection of any possible relationship specifically focused on the hows-and-whys.

Researchers report results based on the examination of one of those ever-so-impressive Scandinavian population registries that have moved science forward in many, many different areas (see here for example). This time around it was the Danish National Patient Register and the inclusion of data from "1 291 679 individuals... born in Denmark and followed up in our population cohort (approximately 15 million person-years)." Over 43,000 individuals showed a history of febrile seizure - "fits that can happen when a child has a fever" - and over 10,000 had epilepsy. Likewise: "83 735 (6%) cohort members were identified with at least one of the psychiatric disorders of interest" including substance abuse disorders, schizophrenia, mood disorder, anxiety, and personality disorder.

Results: "The risk of any psychiatric disorder was raised in individuals with a history of febrile seizures..., epilepsy..., or both disorders." The magnitude of the risk was categorised as statistically significant in terms of elevation but ranged from between a 10-50% increased risk. Further: "Excess risk of psychiatric illness associated with childhood seizures was present across a range of different disorders, most notably schizophrenia but also anxiety and mood disorders." Authors also opine that further research is needed on this topic with regards to mechanisms pertinent to identifying "potential options for prevention."

Although some caution is always required when one variable (epilepsy) is solely correlated with another (history of recorded psychiatric diagnosis), I am interested in the Dreier findings. I'm interested not only because of the *association* being made between a condition that often has life-changing effects on other often life-changing diagnoses but also because this *association* complements other links being made with epilepsy. I speak of the various studies linking epilepsy to diagnostic labels such as autism and attention-deficit hyperactivity disorder (ADHD) of course (see here and see here for examples) whilst pointing out that ADHD and autism are not to be categorised as mental health conditions. Such links between epilepsy and neurodevelopmental diagnoses are all the more interesting because the presence of labels such as autism and ADHD are also known to manifest elevations in other psychiatric diagnoses such as mood disorder, anxiety and schizophrenia (see here and see here and see here for examples). It's not therefore unreasonable to suspect that there may be some 'over-arching' themes when it comes to epilepsy/febrile seizures 'linking' with various developmental and psychiatric diagnoses.

Minus any sweeping generalisations and being careful how I phrase this, one area that requires a lot more investigation is the neurological effect that epilepsy in particular can have. I speak of the idea that seizures can, in some cases, affect the physical nature of the brain [2] and the question of whether such 'damage' might also then affect the presentation of behaviour akin to the signs and symptoms of a neurodevelopmental or psychiatric diagnosis. I know this is not a particularly palatable line of thinking but it does require further scientific exploration. This is also pertinent to the Dreier study focusing in on childhood seizures and by inference, possible effects on the developing brain. Another area of further investigation is whether the presentation of epilepsy or seizures *might* be part-and-parcel of various syndromes also presenting with neurodevelopmental and/or psychiatric features? We do have some examples of this already (see here) and, given that various genetic syndromes are quite regularly being identified day-by-day, it's another area that could yield some important data.

The aim of the study was a relatively simple one: "to identify whether specific RRBI [restricted and repetitive behaviors and interests] (i.e., stereotyped, self-injurious, compulsive, insistence on sameness, ritualistic, and restricted), as measured by item-level data on the Repetitive Behavior Scale-Revised (RBS-R), can distinguish girls from boys with ASD [autism spectrum disorder]." The sample was a pretty good size - "615 individuals with ASD (507 boys; 82.4%)" - and the findings were rather interesting...

So: "Items that best-discriminated gender were heightened stereotyped behaviors and restricted interests items in boys and compulsive, sameness, restricted, and self-injurious behavior items in girls." The authors add that: "This study is the first to find that girls with ASD may have increased compulsive, sameness, and restricted RRBI compared to boys."

Bearing in mind the care required when talking about sweeping generalisations about 'boy autism' and 'girl autism', the Antezana results do point to a need for further study in this area. Not least because the authors rightly mention how: "Future research should disentangle whether elevated rates of RRBI in girls are central to the presentation of ASD in girls or an epiphenomenon of the high rates of co-occurring disorders (e.g., anxiety) noted in girls." This based on the idea that autism rarely exists in some sort of diagnostic vacuum (see here) and some of that *comorbidity* (if that is the right word to use) could very well be part and parcel of such clinical observations.

Friday, 11 January 2019

The paper by Heléne Sundelin and colleagues [1] provides the blogging fodder today, and research pertinent to the question: "Are women with autism at an increased risk of adverse pregnancy outcomes?" The short answer to the question is yes: "Maternal autism is associated with preterm birth, likely due to an increased frequency of medically indicated preterm births, but also with other adverse pregnancy outcomes, suggesting a need for extra surveillance during prenatal care."

It was refreshing to read the results from Sundelin et al (a research group who are no strangers to autism research) because this was a study devoted to looking at women with autism / autistic women and their pregnancy outcomes. It was distinct from other research on maternal pregnancy outcomes and offspring autism more traditionally seen in the peer-reviewed research literature and covered on this blog (see here and see here for examples).

The source material for the Sundelin study was the Swedish Medical Birth Registry (yes, one of those fantastic Scandinavian population registries again) and records of "2,198 births to 1,382 women with autism and 877,742 births to 503,846 women never diagnosed with autism." When comparing the groups across various different measures including preterm delivery ("defined as <37 completed weeks of gestation"), tobacco smoking during pregnancy and the use of various prescription medicines during pregnancy, some interesting trends were observed.

"Women with autism were at an increased risk of preterm birth..., which after stratification, remained for moderately (32 to <37 weeks) preterm birth." Also: "Maternal autism was also linked with an increased risk of elective cesarean delivery in births to women with autism" and "Preeclampsia was more prevalent in mothers with autism."

Although not seemingly affecting many of the 'adverse' pregnancy outcomes examined, researchers also noted that rates of tobacco smoking (light and heavy use) during early pregnancy were elevated in mums with autism, alongside prescription medicine use (antiepileptics, antipsychotics, hypnotics/anxiolytics, antidepressants) being more frequently reported before and during pregnancy compared to non-autistic pregnant mums. Authors reported that "there was no increased risk of adverse pregnancy outcomes except for induction of delivery" but one has to remember that the focus was on pregnancy outcomes - "completed weeks of gestation, mode of delivery, 5-minute Apgar scores, intrauterine growth, stillbirth, and maternal complications (preeclampsia and gestational diabetes)" - and does not say anything about longer term post-pregnancy outcomes. I say this with a few potential 'issues' in mind (see here and see here and see here).

The Sundelin study is by no means perfect - a "limitation is the lack of information on life circumstances" - but does carry the research weight that comes from those extremely well-categorised Scandinavian population registries. The authors conclude that their: "results suggest a need for individual prenatal care for women with autism, weighing pros and cons for continuation of psychotropic medication, with a better understanding of the difficulties related to autism, especially regarding the communication with health care professionals." Who am I to argue with them?

ABOUT AUTISM SPECTRUM CONDITIONS

Autism or autism spectrum conditions describe several presentations characterised by core issues with social affect and stereotyped or repetitive actions. Diagnosis is made by observation and analysis of developmental history. These are heterogeneous conditions which can carry various co-morbidities and whilst described as life-long are affected by age and maturation. Autism means different things to different people. To some it means a need for life-long support. To others it is part of the varied tapestry of humanity. To all it means a need to foster a welcoming society with appropriate support and opportunities.